Investigating the Impact of Crohn’s Disease on the Bioaccessibility of a Lipid-Based Formulation with an In Vitro Dynamic Gastrointestinal Model

Effinger, Angela; McAllister, Mark; Tomaszewska, Irena; O’Driscoll, Caitriona M.; Taylor, M.R.S.; Gomersall, Steve; Heaton, James; Smith, Kieran L; Sarceviča, Inese; Young, Sam L; Fotaki, Nikoletta

doi:10.1021/acs.molpharmaceut.0c00807

Cited by 8 publications

(7 citation statements)

References 72 publications

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“…The TIM-1 model is programmed to evaluate drug product behavior in fasted, fed, and PPI conditions. 19 , 28 , 29 Depending on the chosen clinical condition (PPI, fed), specific experimental protocol is executed. Fasted state is simulated by implementing a predefined pH curve controlled by secretion of 1 M HCl into the gastric compartment.…”

Section: Methodsmentioning

confidence: 99%

“…At the end of the jejunal and ileal compartments, a lipid filtration system is installed to separate the dissolved amount of drug from these compartments and evaluate the amount of drug available for drug absorption (i.e., the bioaccessible fraction of drug). The TIM-1 model is programmed to evaluate drug product behavior in fasted, fed, and PPI conditions. ,, Depending on the chosen clinical condition (PPI, fed), specific experimental protocol is executed. Fasted state is simulated by implementing a predefined pH curve controlled by secretion of 1 M HCl into the gastric compartment.…”

Section: Methodsmentioning

confidence: 99%

“…The gastric emptying half-life of emptying to duodenum is approximately 20 and 80 min for fasted and fed state conditions, respectively. For more information about the TIM-1 settings and the determination of bioaccessible fraction, the reader is referred to external literature. , The bioaccessible fraction was determined by withdrawing samples from the filtrate (at the end of the jejunum and ileum compartment) and these samples were, subsequently, analyzed by HPLC. The expression of the bioaccessible fraction can be depicted in a cumulative or noncumulative order to observe how much drug will become available as a function of time.…”

Section: Methodsmentioning

confidence: 99%

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Effect of Food and a Proton-Pump Inhibitor on the Absorption of Encorafenib: An In Vivo–In Vitro–In Silico Approach

et al. 2023

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Encorafenib is a kinase inhibitor indicated for the treatment of patients with BRAF mutant melanoma and BRAF mutant metastatic colorectal cancer. To understand the effect of food and coadministration with a proton-pump inhibitor (PPI), in vitro, in vivo, and in silico data were generated to optimize the clinical dose, evaluate safety, and better understand the oral absorption process under these conditions. Study 1 evaluated the effect of food on the plasma pharmacokinetics, safety, and tolerability after a single oral dose of encorafenib 100 mg. Study 2 evaluated the same end points with coadministration of encorafenib and rabeprazole (PPI perpetrator). The in vitro gastrointestinal TIM-1 model was used to investigate the release of encorafenib and the amount available for absorption under different testing conditions (fasted, fed, and with the use of a PPI). The fasted, fed, and PPI states were predicted for the encorafenib commercial capsule in GastroPlus 9.8. In study 1, both AUC inf and AUC last decreased by 4% with the administration of a high-fat meal. The C max was 36% lower than with fasted conditions. All 3 exposure parameters in study 2 (AUC inf , AUC last , and C max ) had mean changes of <10% when encorafenib was coadministered with a PPI. Using the in vitro gastrointestinal simulator TIM-1, the model demonstrated a similar release of drug, as the bioaccessible fraction, in the 3 conditions was equal (≥80%), predicting no PPI or food effect for this drug formulation. The modeling in GastroPlus 9.8 demonstrated complete absorption of encorafenib when formulated as an amorphous solid dispersion. To obtain these results, it was crucial to integrate the amorphous solubility of the drug that shows a 20-fold higher solubility at pH 6.8 compared with crystalline solubility. The increased amorphous solubility is likely the reason no PPI effect was observed compared with fasted state conditions. The prolongation in gastric emptying in the fed state resulted in delayed plasma T max for encorafenib. No dose adjustment is necessary when encorafenib is administered in the fed state or when coadministered with a PPI. Both the TIM-1 and physiologically based pharmacokinetic model results were consistent with the observed clinical data, suggesting that these will be valuable tools for future work.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Effect of Food and a Proton-Pump Inhibitor on the Absorption of Encorafenib: An In Vivo–In Vitro–In Silico Approach

et al. 2023

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“…Fresenius PlasmaFlux P1 filters (Germany) with 0.3 m 2 effective surface area and a cutoff pore size of 50 nm were used with the TIM-1 system, and a new set of filters was used for each experiment. All the solutions for use with the TIM-1 system were prepared as described by Effinger et al…”

Section: Methodsmentioning

confidence: 99%

Digitalizing the TIM-1 Model using Computational Approaches–Part One: TIM-1 Data Explorer

Sarcevica,

Hens,

Tomaszewska

et al. 2023

Mol. Pharmaceutics

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The TIM-1 gastrointestinal model is one of the most advanced in vitro systems currently available for biorelevant dissolution testing. This technology, the initial version of which was developed nearly 30 years ago and has been subject to a number of significant updates over this period, simulates the dynamic environment of the human gastrointestinal tract, including pH, transfer times, secretion of bile, enzymes, and electrolytes. In the pharmaceutical industry, the TIM-1 system is used to support drug product design and provide a biopredictive assessment of drug product performance. Typically, the bioaccessibility data sets generated by TIM-1 experiments are used to qualitatively compare formulation performance, and the use of bioaccessibility data as inputs for physiologically based pharmacokinetic (PBPK) modeling for quantitative predictions is limited. To expand the utility of the TIM-1 model beyond standard bioaccessibility measurements (which define the fraction available for absorption), we have developed a computational tool, TIM-1 Data Explorer, to describe the fluid and mass balance within the TIM-1 system. The use of this tool allows a detailed inspection and in-depth interpretation of the experimental data. In addition to mass balance calculation, this model also can be used to describe the critical processes a drug substance would undergo during a TIM-1 experiment, such as dissolution, precipitation on transfer from the stomach to duodenum, and redissolution. The TIM-1 Data Explorer was validated in two case studies. In the first case study with paracetamol, we have shown the ability of the simulator to adequately describe mass transfer events within the TIM-1 system, and in the second study with a weakly basic in-house compound, PF-07059013, the TIM-1 Data Explorer was successfully used to describe dissolution and precipitation processes.

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“…Bile acids identity and percentages in porcine bile used in TIM-1 are in line with previous findings. 28 Bile acids concentrations in the duodenal compartment (Fig. 8A) and in the jejunal compartment (Fig.…”

Section: Bile Acids In Tim-1 Duodenal and Jejunal Compartmentsmentioning

confidence: 97%

In Vitro Simulation of the Environment in the Upper Gastrointestinal Lumen After Drug Administration in the Fed State Using the TIM-1 System and Comparison With Luminal Data in Adults

Pentafragka

Tomaszewska

Bellmann

et al. 2022

Journal of Pharmaceutical Sciences

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Investigating the Impact of Crohn’s Disease on the Bioaccessibility of a Lipid-Based Formulation with an In Vitro Dynamic Gastrointestinal Model

Cited by 8 publications

References 72 publications

Effect of Food and a Proton-Pump Inhibitor on the Absorption of Encorafenib: An In Vivo–In Vitro–In Silico Approach

Effect of Food and a Proton-Pump Inhibitor on the Absorption of Encorafenib: An In Vivo–In Vitro–In Silico Approach

Digitalizing the TIM-1 Model using Computational Approaches–Part One: TIM-1 Data Explorer

In Vitro Simulation of the Environment in the Upper Gastrointestinal Lumen After Drug Administration in the Fed State Using the TIM-1 System and Comparison With Luminal Data in Adults

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